Tuberculosis (TB), the disease due to Mycobacterium tuberculosis (M.tb) is the leading cause of death due to a single pathogen, killing 1-2 million and newly diagnosed in 8-9 million people each year. By far, the most common form of TB develops in the lungs. Pulmonary TB occurs in the face of intact host immunity and has distinctive pathologic phenotypic traits including granuloma necrosis, neutrophil influx, and cavitation. Here, for the first time, we use Diversity Outbred (DO) mice, to help understand how host genetics influence pulmonary TB. We hypothesize that granuloma-specific phenotypes of pulmonary TB reflect pathways of genetic control. We use an innovative multidisciplinary systems approach to capture, quantify, and analyze biologically relevant disease features of pulmonary TB. The results from this proposal will yield novel information regarding pulmonary TB in genetically diverse populations. Results from these studies will also provide the foundation for future, more extensive work determining predictive signatures of disease, therapeutic, and vaccination responses.